Developmental history and gender are thought to be key mediating factors in drug addiction, affecting initial drug use, escalation to abuse, and relapse. Developmental insults can affect structural and neurochemical elements that are directly involved in the reinforcing properties of drugs, or they can perturb systems that modulate the response to stressors and aversive stimuli and thus, indirectly affect drug use. With respect to addiction vulnerability, an understudied developmental insult is prenatal and early postnatal exposure to and withdrawal from drugs of abuse. This is particularly relevant for developmental opiate exposure. The Center for Substance Abuse Treatment recommends that opiate-dependent pregnant women be maintained on opiate substitution therapy throughout pregnancy to minimize the health risks to the mother and fetus that are associated with heroin use. In addition to the direct effects of opiate, a prolonged and stressfulwithdrawal from the opiates occurs in the neonate (abstinence syndrome), which can further act as a developmental insult. Numerous published studies have reported that gender influences the long-term consequences of developmental insults and preliminary studies have revealed that gender differentially affects the consequences of prenatal opiate exposure on measures of adult anxiety behavior and pain sensitivity. However, there has not been a systematic study of how prenatal drug exposure, and the accompanying stress of postnatal opiate withdrawal, interact with gender to affect abuse liability in adulthood, the goal of this research proposal. Subjects will originate from female rats that are made dependent on a long-acting synthetic opiate one month prior to breeding, with treatment through parturition. After birth the pups will be fostered to drug-naive mothers and undergo opiate withdrawal. In adulthood, studies will determine if prenatal opiate exposed male and female rats have differential sensitivity to drug-induced activation and adaptation of the hypothalamic-pituitary-adrenal axis; opiate-withdrawal enhanced anxiety, pain sensitivity, and place aversion; and increased acquisition and cue-induced reinstatement of cocaine and heroin self-administration.